Pull Rosiglitazone, FDA Reviewers Urge

WASHINGTON -- Two FDA reviewers have recommended that the diabetes drug rosiglitazone (Avandia) be pulled from the market because of its link to major cardiac events.

The recommendations were released as part of a report from the Senate Finance Committee on the controversial drug. While rosiglitazone works as well as its competitor pioglitazone (Actos), the report concluded, use of the drug is responsible for a "substantial excess number" of heart attacks and heart failure cases that would not have occurred if patients were taking pioglitazone instead.

"Rosiglitazone should be removed from the market," concluded David Graham, MD, and Kate Gelperin, MD, both epidemiologists with the FDA.

Graham, who has developed a reputation as a safety crusader and whistle blower critical of the agency's postmarket drug safety monitoring record, also raised early concerns about the anti-inflammatory drug Vioxx, which was subsequently removed from the market.

In their report, Senate Finance Committee chairman Max Baucus (D-Mont.) and ranking Republican Sen. Charles Grassley of Iowa suggest that GlaxoSmithKline (GSK) was aware of the cardiac risks associated with diabetes drug rosiglitazone years before the evidence became public.

The drugmaker should have warned patients and the FDA about its concerns, but instead "intimidated independent physicians, focused on strategies to minimize findings that rosiglitazone may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk," the senators wrote in a letter to FDA Commissioner Margaret Hamburg.

In a response published on its Web site, GSK rejected the report and said the report is inconsistent with "rigorous scientific evidence supporting the safety of the drug."

The rosiglitazone saga began in 2007, when a meta-analysis of data from 42 clinical trials -- led by Steven Nissen, MD, of the Cleveland Clinic -- found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with the drug.

The alarming study result prompted the FDA to convene a safety panel of outside experts. The panel voted 22 to 1 that rosiglitazone should not be pulled from the market, but also voted 20 to 3 that rosiglitazone increases the risk of a heart attack.

Shortly afterward, the FDA added a boxed warning to rosiglitazone to address the myocardial ischemia risk, and asked GSK to perform a cardiovascular safety trial, called TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation), to compare Avandia to other diabetes treatments such as pioglitazone (ACTOS). That trial is ongoing.

Around the same time, Baucus and Grassley began investigating how the FDA has handled rosiglitazone and whether GSK knew about the risk of heart attacks and heart failure that their drug posed.

Since 2007, the lawmakers have reviewed hundreds of thousands of pages of internal GSK documents and have spoken with GSK employees and anonymous whistle blowers, they said in a press release announcing the findings of their two-year investigation.

According to a letter Baucus and Grassley sent to FDA Commissioner Margaret Hamburg, MD, their review uncovered an "alarming" 2008 analysis conducted by two FDA safety reviewers who examined all available studies comparing rosiglitazone to pioglitazone.

According to Baucus and Grassley, the reviewers concluded:

"[T]here is no evidence that rosiglitazone confers any unique health benefits over pioglitazone while there is strong evidence that rosiglitazone confers an increased risk of [heart attacks] and heart failure compared to pioglitazone."

The reviewers determined that rosiglitazone is responsible for about 500 additional heart attacks, and 300 additional cases of heart failure each month than would occur if pioglitazone were used exclusively.

Regarding the ongoing TIDE trial, the reviewers said "any proposed head-to-head trial of rosiglitazone versus pioglitazone would be unethical and exploitative," given their finding that while both drugs come with a risk for heart attack, that risk is substantially greater with rosiglitazone.

"After reading these documents, we would like to know what steps the FDA has taken to protect patients in the TIDE trial, and why this trial is allowed to continue," the senators told Hamburg in their letter.

Defending the TIDE trial, GSK said it "has been approved by an independent review board and appropriate safety boards that are responsible for assessing the safety of conducting the trial."

"The scientific evidence simply does not establish that Avandia increases cardiovascular ischemic risk or causes myocardial ischemic events," the company added in its press release.

Grassley also criticized the setup of the FDA's postmarketing review process, in which the same investigators who approved the drug are responsible for monitoring its use by the public.

"It doesn't make any sense to have these experts, who study drugs after they have been on the market for several years, under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision," Grassley wrote.

"The Avandia case may be the most alarming example of the problem with this setup."

FDA spokeswoman Karen Riley said, "The FDA takes very seriously concerns and issues raised in the recent inquiry from Sens. Baucus and Grassley."

Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, issued a memo in December 2009 requesting that all appropriate offices within the Center rapidly evaluate the new data with the aim of presenting it to an FDA Advisory Committee in the summer of 2010, Riley said in a statement.

The agency posted an announcement about the July meeting on its Web site Monday. It will combine a panel of endocrinology and metabolic drug specialists with drug safety experts to examine the rosiglitazone data that has been collected since 2007.

"FDA awaits the recommendations of the advisory committee, and in the meantime Dr. Hamburg plans to meet with FDA scientists and outside experts to gain a full understanding and awareness of all of the data and issues involved," Riley said.